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Aging Cell Dec 2022Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the...
Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice receiving both drugs was neither higher nor lower than that seen previously in Rapa only, perhaps reflecting the limited survival benefits seen in prior cohorts of females receiving Aca alone. Capt led to a significant, though small (4% or 5%), increase in female lifespan. Capt also showed some possible benefits in male mice, but the interpretation was complicated by the unusually low survival of controls at one of the three test sites. BD seemed to produce a small (2%) increase in females, but only if the analysis included data from the site with unusually short-lived controls. None of the other 4 tested agents led to any lifespan benefit. The C2017 ITP dataset shows that combinations of anti-aging drugs may have effects that surpass the benefits produced by either drug used alone, and that additional studies of captopril, over a wider range of doses, are likely to be rewarding.
Topics: Mice; Male; Female; Animals; Acarbose; Sirolimus; Captopril; Longevity; Aging
PubMed: 36179270
DOI: 10.1111/acel.13724 -
Frontiers in Oncology 2023International chemoprevention preferences and approaches in Lynch syndrome (LS) and associated polyposis, including Familial adenomatous polyposis (FAP) and attenuated...
BACKGROUND
International chemoprevention preferences and approaches in Lynch syndrome (LS) and associated polyposis, including Familial adenomatous polyposis (FAP) and attenuated FAP (AFAP) have not been previously explored.
AIM
To describe current chemoprevention strategies for patients with LS or FAP/AFAP (referred to collectively as FAP) practiced by members of four international hereditary cancer societies through administration of a survey.
RESULTS
Ninety-six participants across four hereditary gastrointestinal cancer societies responded to the survey. Most respondents (91%, 87/96) completed information regarding their demographics and practice characteristics relating to hereditary gastrointestinal cancer and chemoprevention clinical practices. Sixty-nine percent (60/87) of respondents offer chemoprevention for FAP and/or LS as a part of their practice. Of the 75% (72/96) of survey respondents who were eligible to answer practice-based clinical vignettes based off of their responses to ten barrier questions regarding chemoprevention, 88% (63/72) of those participants completed at least one case vignette question to further characterize chemoprevention practices in FAP and/or LS. In FAP, 51% (32/63) would offer chemoprevention for rectal polyposis, with sulindac - 300 mg (18%, 10/56) and aspirin (16%, 9/56) being the most frequently selected options. In LS, 93% (55/59) of professionals discuss chemoprevention and 59% (35/59) frequently recommend chemoprevention. Close to half of the respondents (47%, 26/55) would recommend beginning aspirin at time of commencement of the patient's first screening colonoscopy (usually at age 25yrs). Ninety-four percent (47/50) of respondents would consider a patient's diagnosis of LS as an influential factor for aspirin use. There was no consensus on the dose of aspirin (≤100 mg, >100 mg - 325 mg or 600 mg) to offer patients with LS and there was no agreement on how other factors, such as BMI, hypertension, family history of colorectal cancer, and family history of heart disease, would affect the recommendation for aspirin use. Possible harm among older patients (>70 years) was identified as the most common reason to discourage aspirin use.
CONCLUSION
Although chemoprevention is widely discussed and offered to patients with FAP and LS by an international group of hereditary gastrointestinal cancer experts, there is significant heterogeneity in how it is applied in clinical practice.
PubMed: 37293588
DOI: 10.3389/fonc.2023.1141810 -
Analytical and Bioanalytical Chemistry Sep 2022Cyclodextrins (CDs) as a pseudophase in pseudophase-to-pseudophase microextraction (PME) in capillary zone electrophoresis (CZE) are proposed. In this PME mode called CD...
Cyclodextrins (CDs) as a pseudophase in pseudophase-to-pseudophase microextraction (PME) in capillary zone electrophoresis (CZE) are proposed. In this PME mode called CD to admicelle ME, a long plug of dilute analyte solution prepared in cetyltrimethylammonium bromide (CTAB) at the critical micellar concentration was injected into the capillary. This formed CTAB admicelles at the interface between the solution and the negatively charged capillary surface, where the analytes were trapped. The injection of CD solution released the admicelles and the analytes from the capillary surface due to the formation of stable CD/CTAB inclusion complexes. The analytes are concentrated at the CD front during injection and voltage separation. Various neutral CDs were found to be effective for CD to admicelle ME. To implement this in-line sample concentration technique in CZE, CD concentration, sample injection time, and sample:CD solution injection ratio were optimized. The optimized conditions for five model anionic analytes, namely, 4-bromophenol, sulindac, sulfamethizole, 4-vinylbenzoic acid, and succinylsulfathiazole, were 20 mM α-CD in 20 mM sodium tetraborate (pH 9.2) solution, sample injection time of 370 s, and CD:sample injection ratio of 1:2. The sensitivity enhancement factors (SEFs) were between 112 and 168. The SEFs of sulindac and sulfamethizole in particular were similar to previously published off-line microextraction techniques, which are typically time-consuming. The calculated values of LOQ, intra-/inter-day (n = 6/n = 10, 3 days) repeatability, and linearity (R) of CD to admicelle ME were 0.0125-0.05 µg/mL, 1.5-4.6%, 1.8-4.8%, and ≥0.999, respectively. Finally, the potential of CD to admicelle ME to the analysis of artificial urine samples was demonstrated.
Topics: Cetrimonium; Cyclodextrins; Electrophoresis, Capillary; Hydrogen-Ion Concentration; Sulfamethizole; Sulindac
PubMed: 35978220
DOI: 10.1007/s00216-022-04230-0 -
Acta Pharmacologica Sinica Jan 2015Retinoid X receptor-α (RXRα), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and... (Review)
Review
Retinoid X receptor-α (RXRα), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and therapeutic applications in cancer, metabolic disorders and neurodegenerative diseases. Despite the fact that the RXR-based drug Targretin (bexarotene) is currently used for treating human cutaneous T-cell lymphoma and the fact that RXRα ligands (rexinoids) show beneficial effects in the treatment of cancer and diseases, the therapeutic potential of RXRα remains unexplored. In addition to its conventional transcription regulation activity in the nucleus, RXRα can act in the cytoplasm to modulate important biological processes, such as mitochondria-dependent apoptosis, inflammation, and phosphatidylinositol 3-kinase (PI3K)/AKT-mediated cell survival. Recently, new small-molecule-binding sites on the surface of RXRα have been identified, which mediate the regulation of the nongenomic actions of RXRα by a class of small molecules derived from the nonsteroidal anti-inflammatory drug (NSAID) Sulindac. This review discusses the emerging roles of the nongenomic actions of RXRα in the RXRα signaling network, and their possible implications in cancer, metabolic and neurodegenerative disorders, as well as our current understanding of RXRα regulation by targeting alternate binding sites on its surface.
Topics: Animals; Binding Sites; Endocrine Disruptors; Humans; PPAR gamma; Retinoid X Receptor alpha
PubMed: 25434990
DOI: 10.1038/aps.2014.109 -
Journal of Clinical Medicine May 2022We report a retrospective case series of six Hispanic children with tumors treated with metronomic chemotherapy. The six cases comprised one rhabdoid tumor of the... (Review)
Review
We report a retrospective case series of six Hispanic children with tumors treated with metronomic chemotherapy. The six cases comprised one rhabdoid tumor of the kidney, one ependymoma, two medulloblastomas, one neuroblastoma, and a type II neurocytoma of the spine. Treatment included oral cyclophosphamide daily for 21 days alternating with oral etoposide daily for 21 days in a backbone of daily valproic acid and celecoxib. In one case, celecoxib was substituted with sulindac. Of the six patients, three showed complete responses, and all patients showed some response to metronomic therapy with only minor hematologic toxicity. One patient had hemorrhagic gastritis likely associated with NSAIDs while off prophylactic antacids. These data add to a growing body of evidence suggesting that continuous doses of valproic acid and celecoxib coupled with alternating metronomic chemotherapy of agents such as etoposide and cyclophosphamide can produce responses in pediatric tumors relapsing to conventional dose chemotherapy.
PubMed: 35628975
DOI: 10.3390/jcm11102849 -
Cancer Prevention Research... Aug 2017Sulindac is an NSAID that can provide effective chemoprevention for colorectal cancer. In this study, alternative dosing regimens of sulindac were evaluated for their...
Sulindac is an NSAID that can provide effective chemoprevention for colorectal cancer. In this study, alternative dosing regimens of sulindac were evaluated for their chemoprevention effectiveness in the azoxymethane-treated A/J mouse model of colorectal cancer. High-resolution endoscopic optical coherence tomography was utilized to time-serially measure tumor number and tumor burden in the distal colon as the biological endpoints. Four treatment groups were studied: (i) daily for 20 weeks (sulindac-daily); (ii) for 2 weeks, then no sulindac for 2 weeks, cycle repeated 5 times (sulindac-2); (iii) for 10 weeks ("on"), then no sulindac for 10 weeks ("off"; sulindac-10); and (iv) no sulindac (sulindac-none). Sulindac-2 and sulindac-daily had statistically significantly lower final tumor counts and slopes (change in number of tumors per week) when compared with sulindac-none ( < 0.0001). All of the treatment groups had statistically significantly lower final tumor burdens and slopes when compared with sulindac-none ( < 0.001). There was a prolonged latency period in the sulindac-10 group, with no significant difference between the "off" portion of this treatment and sulindac-none. These results suggest that, although daily doses of sulindac provide the most optimal effects, intermittent doses of sulindac in a 50% duty cycle with an overall 4-week period (sulindac-2 model) can provide highly effective chemoprevention of colorectal cancer in this model. After cessation of sulindac treatment (sulindac-10 "off"), there is no evidence of either a persistent chemopreventive effect or a rebound effect. .
Topics: Animals; Antineoplastic Agents; Azoxymethane; Carcinogens; Chemoprevention; Colorectal Neoplasms; Disease Models, Animal; Female; Mice; Sulindac
PubMed: 28611038
DOI: 10.1158/1940-6207.CAPR-17-0038 -
Oncotarget Jul 2016Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we...
Tumor cells acquire metastasis-associated (MA) phenotypes following genetic alterations in them which cause deregulation of different signaling pathways. Earlier, we reported that an upregulation of the Wnt-beta-catenin pathway (WP) is one of the genetic salient features of triple-negative breast cancer (TNBC), and WP signaling is associated with metastasis in TNBC. Using cBioPortal, here we found that collective % of alteration(s) in WP genes, CTNNB1, APC and DVL1 among breast-invasive-carcinomas was 21% as compared to 56% in PAM50 Basal. To understand the functional relevance of WP in the biology of heterogeneous/metastasizing TNBC cells, we undertook this comprehensive study using 15 cell lines in which we examined the role of WP in the context of integrin-dependent MA-phenotypes. Directional movement of tumor cells was observed by confocal immunofluorescence microscopy and quantitative confocal-video-microscopy while matrigel-invasion was studied by MMP7-specific casein-zymography. WntC59, XAV939, sulindac sulfide and beta-catenin siRNA (1) inhibited fibronectin-directed migration, (2) decreased podia-parameters and motility-descriptors, (3) altered filamentous-actin, (4) decreased matrigel-invasion and (5) inhibited cell proliferation as well as 3D clonogenic growth. Sulindac sulfide and beta-catenin siRNA decreased beta-catenin/active-beta-catenin and MMP7. LWnt3ACM-stimulated proliferation, clonogenicity, fibronectin-directed migration and matrigel-invasion were perturbed by WP-modulators, sulindac sulfide and GDC-0941. We studied a direct involvement of WP in metastasis by stimulating brain-metastasis-specific MDA-MB231BR cells to demonstrate that LWnt3ACM-stimulated proliferation, clonogenicity and migration were blocked following sulindac sulfide, GDC-0941 and beta-catenin knockdown. We present the first evidence showing a direct functional relationship between WP activation and integrin-dependent MA-phenotypes. By proving the functional relationship between WP activation and MA-phenotypes, our data mechanistically explains (1) why different components of WP are upregulated in TNBC, (2) how WP activation is associated with metastasis and (3) how integrin-dependent MA-phenotypes can be regulated by mitigating the WP.
Topics: Adenomatous Polyposis Coli Protein; Brain Neoplasms; Carcinoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dishevelled Proteins; Female; Fibronectins; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 3-Ring; Humans; Indazoles; Integrins; Matrix Metalloproteinase 7; Microscopy, Confocal; Microscopy, Fluorescence; Microscopy, Video; Mutation; Phenotype; RNA Interference; RNA, Small Interfering; Sulfonamides; Sulindac; Triple Negative Breast Neoplasms; Up-Regulation; Wnt Proteins; Wnt Signaling Pathway; beta Catenin
PubMed: 27281609
DOI: 10.18632/oncotarget.8988 -
Carcinogenesis Dec 2022Malignant mesothelioma (MM) is an incurable cancer of the serosal lining that is often caused by exposure to asbestos. Therefore, novel agents for the prevention and...
Malignant mesothelioma (MM) is an incurable cancer of the serosal lining that is often caused by exposure to asbestos. Therefore, novel agents for the prevention and treatment of this disease are urgently needed. Asbestos induces the release of pro-inflammatory cytokines such as IL-1β and IL-6, which play a role in MM development. IL-6 is a component of the JAK-STAT3 pathway that contributes to inflammation-associated tumorigenesis. Glycoprotein 130 (gp130), the signal transducer of this signaling axis, is an attractive drug target because of its role in promoting neoplasia via the activation of downstream STAT3 signaling. The anticancer drug, SC144, inhibits the interaction of gp130 with the IL-6 receptor (IL6R), effectively blunting signaling from this inflammatory axis. To test whether the inflammation-related release of IL-6 plays a role in the formation of MM, we evaluated the ability of SC144 to inhibit asbestos-induced carcinogenesis in a mouse model. The ability of sulindac and anakinra, an IL6R antagonist/positive control, to inhibit MM formation in this model was tested in parallel. Asbestos-exposed Nf2+/-;Cdkn2a+/- mice treated with SC144, sulindac or anakinra showed significantly prolonged survival compared to asbestos-exposed vehicle-treated mice. STAT3 activity was markedly decreased in MM specimens from SC144-treated mice. Furthermore, SC144 inhibited STAT3 activation by IL-6 in cultured normal mesothelial cells, and in vitro treatment of MM cells with SC144 markedly decreased the expression of STAT3 target genes. The emerging availability of newer, more potent SC144 analogs showing improved pharmacokinetic properties holds promise for future trials, benefitting individuals at high risk of this disease.
Topics: Mice; Animals; Mesothelioma, Malignant; Interleukin-6; Sulindac; Interleukin 1 Receptor Antagonist Protein; Cytokine Receptor gp130; Asbestos; Carcinogenesis; Inflammation; Chemoprevention; Mesothelioma
PubMed: 36355620
DOI: 10.1093/carcin/bgac089 -
Cancer Research Communications Feb 2022Adenomatous polyposis coli (APC) truncations occur in many colorectal cancers and are often associated with immune infiltration. The aim of this study was to determine...
UNLABELLED
Adenomatous polyposis coli (APC) truncations occur in many colorectal cancers and are often associated with immune infiltration. The aim of this study was to determine whether a combination of Wnt inhibition with anti-inflammatory (sulindac) and/or proapototic (ABT263) drugs can reduce colon adenomas. and doublecortin-like kinase 1 () mice were exposed to dextran sulphate sodium (DSS) in their drinking water to promote the formation of colon adenomas. Mice were then treated with either a Wnt-signaling antagonist pyrvinium pamoate (PP), an anti-inflammatory agent sulindac or proapoptotic compound ABT263 or a combination of PP+ABT263, or PP+sulindac. Colon adenoma frequency, size, and T-cell abundance were measured. DSS treatment resulted in significant increases in colon adenoma number ( < 0.001, > 5) and burden in ( < 0.01, > 5) and ( < 0.02, > 5) mice. There was no effect on adenomas following treatment with PP in combination with ABT263. Adenoma number and burden were reduced with PP+sulindac treatment in ; mice ( < 0.01, > 17) and in mice ( < 0.001, > 7) treated with sulindac or PP+sulindac with no detectable toxicity. PP treatment of mice increased the frequency of CD3 cells in the adenomas. The combination of Wnt pathway inhibition with sulindac was more effective in ; mice and provides an opportunity for killing -mutant colon adenoma cells, indicating a strategy for both colorectal cancer prevention and potential new treatments for patients with advanced colorectal cancer. Outcomes from the results of this study may be translatable to the clinic for management of FAP and other patients with a high risk of developing colorectal cancer.
SIGNIFICANCE
Colorectal cancer is one of the most common cancers worldwide with limited therapeutic options. APC and other Wnt signaling mutations occur in the majority of colorectal cancers but there are currently no Wnt inhibitors in the clinic. The combination of Wnt pathway inhibition with sulindac provides an opportunity for killing -mutant colon adenoma cells and suggests a strategy for colorectal cancer prevention and new treatments for patients with advanced colorectal cancer.
Topics: Animals; Mice; Adenoma; Adenomatous Polyposis Coli; Anti-Inflammatory Agents, Non-Steroidal; Colonic Neoplasms; Colorectal Neoplasms; Protein Serine-Threonine Kinases; Sulindac
PubMed: 36860494
DOI: 10.1158/2767-9764.CRC-21-0105 -
The Journal of Experimental Medicine May 2017Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription...
Human hepatocellular carcinomas (HCCs), which arise on a background of chronic liver damage and inflammation, express c-Fos, a component of the AP-1 transcription factor. Using mouse models, we show that hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced HCCs, whereas liver-specific c-Fos expression leads to reversible premalignant hepatocyte transformation and enhanced DEN-carcinogenesis. c-Fos-expressing livers display necrotic foci, immune cell infiltration, and altered hepatocyte morphology. Furthermore, increased proliferation, dedifferentiation, activation of the DNA damage response, and gene signatures of aggressive HCCs are observed. Mechanistically, c-Fos decreases expression and activity of the nuclear receptor LXRα, leading to increased hepatic cholesterol and accumulation of toxic oxysterols and bile acids. The phenotypic consequences of c-Fos expression are partially ameliorated by the anti-inflammatory drug sulindac and largely prevented by statin treatment. An inverse correlation between c-FOS and the LXRα pathway was also observed in human HCC cell lines and datasets. These findings provide a novel link between chronic inflammation and metabolic pathways important in liver cancer.
Topics: Animals; Carcinoma, Hepatocellular; Cell Transformation, Neoplastic; Cholesterol; Diethylnitrosamine; Disease Models, Animal; Drosophila Proteins; Liver; Liver Neoplasms; Mice; Proto-Oncogene Proteins c-fos; Repressor Proteins
PubMed: 28356389
DOI: 10.1084/jem.20160935